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Arcasoy, Murat Osman

Overview:

Dr. Arcasoy's research interests include 1)The role of cytokines and cytokine receptors in hematopoietic commitment and lineage-specific differentiation 2) Mechanisms of tissue-specific expression of erythropoietin receptor (EPOR) gene and its role in lineage commitment and lineage-specific differentiation 3) Studies of the molecular basis of familial and congenital myeloproliferative disorders.4). Isolation of novel hematopoietic cytokine-responsive genes and study of their function and regulation 5). Characterization of novel non-hematopoietic functions of EPOR signaling

Dr. Arcasoy's laboratory has been studying the expression, regulation and function of the EPOR gene focusing on the function of naturally occuring mutations of the EPOR gene that result in primary familial and congenital polycythemia as well as the non-hematopoietic expression and functions of EPOR in vascular endothelium, macrophages, cardiac myocytes and cancer cells. We have also been studying global gene expression in erythroid cells from patients with polycythemia vera to better characterize the molecular signature of the disorder and develop new diagnostic tools.

Positions:

Professor of Medicine

Medicine, Hematology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1987

M.D. — Aegean University School of Medicine (Turkey)

Medical Resident, Medicine

State University of New York at Brooklyn

Chief Medical Resident, Medicine

State University of New York at Brooklyn

Hematology Fellow, Medicine

Yale University

Fellow In Medical Oncology, Medicine

Yale University

Grants:

GS US 352 1154

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
December 14, 2016
End Date
January 08, 2022

A Phase 2, Open-label, Translational Biology Study of Momelotinib in Transfusion-Dependent Subjects

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
April 17, 2016
End Date
April 16, 2021

A Randomized, Single-Blind, Multicenter Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat in Subjects with Intermediate-2

Administered By
Duke Cancer Institute
AwardedBy
Janssen Research & Development, LLC
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2021

Gilead GS-US-352-1214

Administered By
Medicine, Cellular Therapy
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
November 08, 2014
End Date
November 07, 2019

Erythropoietin Receptors in Breast Cancer

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2004
End Date
February 28, 2010

Role of Erythropoietin Receptor Signaling in the Heart

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2003
End Date
May 31, 2006

Erythropoietin Receptor Regulation of Erythorpoiesis

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1998
End Date
June 30, 2005
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Publications:

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors.

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.

Authors
Shanavas, M; Popat, U; Michaelis, LC; Fauble, V; McLornan, D; Klisovic, R; Mascarenhas, J; Tamari, R; Arcasoy, MO; Davies, J; Gergis, U; Ukaegbu, OC; Kamble, RT; Storring, JM; Majhail, NS; Romee, R; Verstovsek, S; Pagliuca, A; Vasu, S; Ernst, B; Atenafu, EG; Hanif, A; Champlin, R; Hari, P; Gupta, V
MLA Citation
Shanavas, M, Popat, U, Michaelis, LC, Fauble, V, McLornan, D, Klisovic, R, Mascarenhas, J, Tamari, R, Arcasoy, MO, Davies, J, Gergis, U, Ukaegbu, OC, Kamble, RT, Storring, JM, Majhail, NS, Romee, R, Verstovsek, S, Pagliuca, A, Vasu, S, Ernst, B, Atenafu, EG, Hanif, A, Champlin, R, Hari, P, and Gupta, V. "Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22.3 (March 2016): 432-440.
PMID
26493563
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
22
Issue
3
Publish Date
2016
Start Page
432
End Page
440
DOI
10.1016/j.bbmt.2015.10.005

The clinical and laboratory evaluation of the patient with erythrocytosis.

Erythrocytosis is frequently encountered as an incidental abnormality on laboratory testing that reveals persistent elevation of the hematocrit level (>52% in men and >48% in women). In many cases, erythrocytosis is the manifestation of an underlying cardiopulmonary process, drug-induced due to androgens, or secondary to smoking, rather than a primary bone marrow disorder such as polycythemia vera. A systematic approach to the clinical and laboratory evaluation of each patient is indicated to consider diverse differential diagnosis possibilities and to identify the underlying etiology of erythrocytosis in order to formulate appropriate subspecialist referral and management plans. A thorough medical history and meticulous physical examination supplemented by a focused initial laboratory evaluation will enable the general practitioner to ascertain the etiology of erythrocytosis in the majority of cases. Patients with clinical and laboratory features suggestive of polycythemia vera and those patients without an apparent underlying condition known to cause erythrocytosis benefit from early referral to a hematologist for further specialized diagnostic evaluation and therapy considerations.

Authors
Lee, G; Arcasoy, MO
MLA Citation
Lee, G, and Arcasoy, MO. "The clinical and laboratory evaluation of the patient with erythrocytosis." European journal of internal medicine 26.5 (June 2015): 297-302. (Review)
PMID
25837692
Source
epmc
Published In
European Journal of Internal Medicine
Volume
26
Issue
5
Publish Date
2015
Start Page
297
End Page
302
DOI
10.1016/j.ejim.2015.03.007

Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

Authors
Verstovsek, S; Mesa, RA; Gotlib, J; Levy, RS; Gupta, V; DiPersio, JF; Catalano, JV; Deininger, MWN; Miller, CB; Silver, RT; Talpaz, M; Winton, EF; Harvey, JH; Arcasoy, MO; Hexner, EO; Lyons, RM; Raza, A; Vaddi, K; Sun, W; Peng, W; Sandor, V; Kantarjian, H
MLA Citation
Verstovsek, S, Mesa, RA, Gotlib, J, Levy, RS, Gupta, V, DiPersio, JF, Catalano, JV, Deininger, MWN, Miller, CB, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, EO, Lyons, RM, Raza, A, Vaddi, K, Sun, W, Peng, W, Sandor, V, and Kantarjian, H. "Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I." Haematologica 100.4 (April 2015): 479-488.
PMID
25616577
Source
epmc
Published In
Haematologica
Volume
100
Issue
4
Publish Date
2015
Start Page
479
End Page
488
DOI
10.3324/haematol.2014.115840

Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms

© JNCCN-Journal of the National Comprehensive Cancer Network.The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2V617F and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.

Authors
Stein, BL; Gotlib, J; Arcasoy, M; Nguyen, MH; Shah, N; Moliterno, A; Jamieson, C; Pollyea, DA; Scott, B; Wadleigh, M; Levine, R; Komrokji, R; Klisovic, R; Gundabolu, K; Kropf, P; Wetzler, M; Oh, ST; Ribeiro, R; Paschal, R; Mohan, S; Podoltsev, N; Prchal, J; Talpaz, M; Snyder, D; Verstovsek, S; Mesa, RA
MLA Citation
Stein, BL, Gotlib, J, Arcasoy, M, Nguyen, MH, Shah, N, Moliterno, A, Jamieson, C, Pollyea, DA, Scott, B, Wadleigh, M, Levine, R, Komrokji, R, Klisovic, R, Gundabolu, K, Kropf, P, Wetzler, M, Oh, ST, Ribeiro, R, Paschal, R, Mohan, S, Podoltsev, N, Prchal, J, Talpaz, M, Snyder, D, Verstovsek, S, and Mesa, RA. "Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms." JNCCN Journal of the National Comprehensive Cancer Network 13.4 (January 1, 2015): 424-434. (Review)
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
4
Publish Date
2015
Start Page
424
End Page
434

Lung transplantation in telomerase mutation carriers with pulmonary fibrosis.

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the U.S.A., Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients.

Authors
Silhan, LL; Shah, PD; Chambers, DC; Snyder, LD; Riise, GC; Wagner, CL; Hellström-Lindberg, E; Orens, JB; Mewton, JF; Danoff, SK; Arcasoy, MO; Armanios, M
MLA Citation
Silhan, LL, Shah, PD, Chambers, DC, Snyder, LD, Riise, GC, Wagner, CL, Hellström-Lindberg, E, Orens, JB, Mewton, JF, Danoff, SK, Arcasoy, MO, and Armanios, M. "Lung transplantation in telomerase mutation carriers with pulmonary fibrosis." The European respiratory journal 44.1 (July 2014): 178-187.
PMID
24833766
Source
epmc
Published In
The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology
Volume
44
Issue
1
Publish Date
2014
Start Page
178
End Page
187
DOI
10.1183/09031936.00060014

Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies.

Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.

Authors
Mesa, RA; Kiladjian, J-J; Verstovsek, S; Al-Ali, HK; Gotlib, J; Gisslinger, H; Levy, R; Siulnik, A; Gupta, V; Khan, M; DiPersio, JF; McQuitty, M; Catalano, JV; Hunter, DS; Knoops, L; Deininger, M; Cervantes, F; Miller, C; Vannucchi, AM; Silver, RT; Barbui, T; Talpaz, M; Barosi, G; Winton, EF; Mendeson, E; Harvey, JH; Arcasoy, MO; Hexner, E; Lyons, RM; Paquette, R; Raza, A; Sun, W; Sandor, V; Kantarjian, HM; Harrison, C
MLA Citation
Mesa, RA, Kiladjian, J-J, Verstovsek, S, Al-Ali, HK, Gotlib, J, Gisslinger, H, Levy, R, Siulnik, A, Gupta, V, Khan, M, DiPersio, JF, McQuitty, M, Catalano, JV, Hunter, DS, Knoops, L, Deininger, M, Cervantes, F, Miller, C, Vannucchi, AM, Silver, RT, Barbui, T, Talpaz, M, Barosi, G, Winton, EF, Mendeson, E, Harvey, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Sun, W, Sandor, V, Kantarjian, HM, and Harrison, C. "Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies." Haematologica 99.2 (February 2014): 292-298.
PMID
23911705
Source
pubmed
Published In
Haematologica
Volume
99
Issue
2
Publish Date
2014
Start Page
292
End Page
298
DOI
10.3324/haematol.2013.087650

Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies.

Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.

Authors
Mesa, RA; Kiladjian, JJ; Verstovsek, S; Al-Ali, HK; Gotlib, J; Gisslinger, H; Levy, R; Siulnik, A; Gupta, V; Khan, M; DiPersio, JF; McQuitty, M; Catalano, JV; Hunter, DS; Knoops, L; Deininger, M; Cervantes, F; Miller, C; Vannucchi, AM; Silver, RT; Barbui, T; Talpaz, M; Barosi, G; Winton, EF; Mendeson, E; Harvey, JH; Arcasoy, MO; Hexner, E; Lyons, RM; Paquette, R; Raza, A; Sun, W; Sandor, V; Kantarjian, HM; Harrison, C
MLA Citation
Mesa, RA, Kiladjian, JJ, Verstovsek, S, Al-Ali, HK, Gotlib, J, Gisslinger, H, Levy, R, Siulnik, A, Gupta, V, Khan, M, DiPersio, JF, McQuitty, M, Catalano, JV, Hunter, DS, Knoops, L, Deininger, M, Cervantes, F, Miller, C, Vannucchi, AM, Silver, RT, Barbui, T, Talpaz, M, Barosi, G, Winton, EF, Mendeson, E, Harvey, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Sun, W, Sandor, V, Kantarjian, HM, and Harrison, C. "Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies." Haematologica 99.2 (January 1, 2014): 292-298.
Source
scopus
Published In
Haematologica
Volume
99
Issue
2
Publish Date
2014
Start Page
292
End Page
298
DOI
10.3324/haematol.2013.087650

Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies

Authors
Mesa, RA; Kiladjian, J-J; Verstovsek, S; Al-Ali, HK; Gotlib, J; Gisslinger, H; Levy, R; Siulnik, A; Gupta, V; Khan, M; DiPersio, JF; McQuitty, M; Catalano, JV; Hunter, DS; Knoops, L; Deininger, M; Cervantes, F; Miller, C; Vannucchi, AM; Silver, RT; Barbui, T; Talpaz, M; Barosi, G; Winton, EF; Mendeson, E; Harvey Jr, JH; Arcasoy, MO; Hexner, E; Lyons, RM; Paquette, R; Raza, A; Sun, W; Sandor, V; Kantarjian, HM; Harrison, C
MLA Citation
Mesa, RA, Kiladjian, J-J, Verstovsek, S, Al-Ali, HK, Gotlib, J, Gisslinger, H, Levy, R, Siulnik, A, Gupta, V, Khan, M, DiPersio, JF, McQuitty, M, Catalano, JV, Hunter, DS, Knoops, L, Deininger, M, Cervantes, F, Miller, C, Vannucchi, AM, Silver, RT, Barbui, T, Talpaz, M, Barosi, G, Winton, EF, Mendeson, E, Harvey Jr, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Sun, W, Sandor, V, Kantarjian, HM, and Harrison, C. "Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies." Haematologica 99.2 (2014): 291-298.
Source
scopus
Published In
Haematologica
Volume
99
Issue
2
Publish Date
2014
Start Page
291
End Page
298

Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I.

COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.

Authors
Verstovsek, S; Mesa, RA; Gotlib, J; Levy, RS; Gupta, V; DiPersio, JF; Catalano, JV; Deininger, MWN; Miller, CB; Silver, RT; Talpaz, M; Winton, EF; Harvey, JH; Arcasoy, MO; Hexner, EO; Lyons, RM; Paquette, R; Raza, A; Vaddi, K; Erickson-Viitanen, S; Sun, W; Sandor, V; Kantarjian, HM
MLA Citation
Verstovsek, S, Mesa, RA, Gotlib, J, Levy, RS, Gupta, V, DiPersio, JF, Catalano, JV, Deininger, MWN, Miller, CB, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, EO, Lyons, RM, Paquette, R, Raza, A, Vaddi, K, Erickson-Viitanen, S, Sun, W, Sandor, V, and Kantarjian, HM. "Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I." Haematologica 98.12 (December 2013): 1865-1871.
PMID
24038026
Source
pubmed
Published In
Haematologica
Volume
98
Issue
12
Publish Date
2013
Start Page
1865
End Page
1871
DOI
10.3324/haematol.2013.092155

The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis.

Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100-200 × 10(9)/l, >200 × 10(9)/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan-Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I.

Authors
Verstovsek, S; Mesa, RA; Gotlib, J; Levy, RS; Gupta, V; DiPersio, JF; Catalano, JV; Deininger, M; Miller, C; Silver, RT; Talpaz, M; Winton, EF; Harvey, JH; Arcasoy, MO; Hexner, E; Lyons, RM; Paquette, R; Raza, A; Vaddi, K; Erickson-Viitanen, S; Sun, W; Sandor, V; Kantarjian, HM
MLA Citation
Verstovsek, S, Mesa, RA, Gotlib, J, Levy, RS, Gupta, V, DiPersio, JF, Catalano, JV, Deininger, M, Miller, C, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Vaddi, K, Erickson-Viitanen, S, Sun, W, Sandor, V, and Kantarjian, HM. "The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis." Br J Haematol 161.4 (May 2013): 508-516.
PMID
23480528
Source
pubmed
Published In
British Journal of Haematology
Volume
161
Issue
4
Publish Date
2013
Start Page
508
End Page
516
DOI
10.1111/bjh.12274

The clinical benefit of ruxolitinib across patient subgroups: Analysis of a placebo-controlled, Phase III study in patients with myelofibrosis

Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n=155) or placebo (n=154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, >65years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100g/l), baseline platelet count (100-200×109/l, >200×109/l), baseline palpable spleen size (≤10, >10cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1=lowest, Q4=highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan-Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I. © 2013 John Wiley & Sons Ltd.

Authors
Verstovsek, S; Mesa, RA; Gotlib, J; Levy, RS; Gupta, V; Dipersio, JF; Catalano, JV; Deininger, M; Miller, C; Silver, RT; Talpaz, M; Winton, EF; Harvey, JH; Arcasoy, MO; Hexner, E; Lyons, RM; Paquette, R; Raza, A; Vaddi, K; Erickson-Viitanen, S; Sun, W; Sandor, V; Kantarjian, HM
MLA Citation
Verstovsek, S, Mesa, RA, Gotlib, J, Levy, RS, Gupta, V, Dipersio, JF, Catalano, JV, Deininger, M, Miller, C, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Vaddi, K, Erickson-Viitanen, S, Sun, W, Sandor, V, and Kantarjian, HM. "The clinical benefit of ruxolitinib across patient subgroups: Analysis of a placebo-controlled, Phase III study in patients with myelofibrosis." British Journal of Haematology 161.4 (2013): 508-516.
Source
scival
Published In
British Journal of Haematology
Volume
161
Issue
4
Publish Date
2013
Start Page
508
End Page
516
DOI
10.1111/bjh.12274

Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon? A clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens.

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.8%), and myeloproliferative neoplasm (MPN) or MDS/MPN in 3 (7.3%) cases. The latency from treatment to diagnosis of MN ranged from 9 to 384 months, with a median of 60 months. Of 37 cases with cytogenetic studies, complex abnormalities were detected in 22 (59.5%), -5(q)/-7(q) in 4 (10.8%), other abnormalities in 8 (21.6%), and normal karyotype in 3 (8.1%) cases. Complex abnormalities and -5(q)/-7(q) correlated directly with multiple chemotherapeutic regimens, particularly with combined melphalan/cyclophosphamide. Moreover, the features of cytogenetic abnormalities in our series were significantly different from those with concomitant PCM/MN who had significantly lower complex abnormalities. The latency, skewed proportion of MDS, and bias toward complex cytogenetic abnormalities/unbalanced aberrations of chromosomes 5/7 suggested an alkylating mutagenic effect on pathogenesis of secondary MN. Kaplan-Meier survival analysis demonstrated a median survival of 19 months, which was better than that for therapy-related (t)-MDS/AML. In contrast to t-MDS, the survival in our patients appeared to depend on subtypes of MDS as seen in de novo diseases.

Authors
Reddi, DM; Lu, CM; Fedoriw, G; Liu, Y-C; Wang, FF; Ely, S; Boswell, EL; Louissaint, A; Arcasoy, MO; Goodman, BK; Wang, E
MLA Citation
Reddi, DM, Lu, CM, Fedoriw, G, Liu, Y-C, Wang, FF, Ely, S, Boswell, EL, Louissaint, A, Arcasoy, MO, Goodman, BK, and Wang, E. "Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon? A clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens." Am J Clin Pathol 138.6 (December 2012): 855-866.
PMID
23161720
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
138
Issue
6
Publish Date
2012
Start Page
855
End Page
866
DOI
10.1309/AJCPOP7APGDT9JIU

Erythropoietin receptor contributes to melanoma cell survival in vivo.

Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.

Authors
Kumar, SM; Zhang, G; Bastian, BC; Arcasoy, MO; Karande, P; Pushparajan, A; Acs, G; Xu, X
MLA Citation
Kumar, SM, Zhang, G, Bastian, BC, Arcasoy, MO, Karande, P, Pushparajan, A, Acs, G, and Xu, X. "Erythropoietin receptor contributes to melanoma cell survival in vivo." Oncogene 31.13 (March 29, 2012): 1649-1660.
PMID
21860424
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
31
Issue
13
Publish Date
2012
Start Page
1649
End Page
1660
DOI
10.1038/onc.2011.366

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.

BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

Authors
Verstovsek, S; Mesa, RA; Gotlib, J; Levy, RS; Gupta, V; DiPersio, JF; Catalano, JV; Deininger, M; Miller, C; Silver, RT; Talpaz, M; Winton, EF; Harvey, JH; Arcasoy, MO; Hexner, E; Lyons, RM; Paquette, R; Raza, A; Vaddi, K; Erickson-Viitanen, S; Koumenis, IL; Sun, W; Sandor, V; Kantarjian, HM
MLA Citation
Verstovsek, S, Mesa, RA, Gotlib, J, Levy, RS, Gupta, V, DiPersio, JF, Catalano, JV, Deininger, M, Miller, C, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Vaddi, K, Erickson-Viitanen, S, Koumenis, IL, Sun, W, Sandor, V, and Kantarjian, HM. "A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis." N Engl J Med 366.9 (March 1, 2012): 799-807.
PMID
22375971
Source
pubmed
Published In
The New England journal of medicine
Volume
366
Issue
9
Publish Date
2012
Start Page
799
End Page
807
DOI
10.1056/NEJMoa1110557

Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors.

BACKGROUND: High-dose erythropoiesis-stimulating agents (ESA) for anemia of chronic kidney disease (CKD) have been associated with adverse clinical outcomes and do not always improve erythropoiesis. We hypothesized that high-dose ESA requirement would be associated with elevated inflammatory biomarkers, decreased adipokines, and increased circulating, endogenous soluble erythropoietin receptors (sEpoR). METHODS: A cross-sectional cohort of anemic 32 CKD participants receiving ESA were enrolled at a single center and cytokine profiles, adipokines, and sEpoR were compared between participants stratified by ESA dose requirement (usual-dose darbepoetin-α (< 1 μg/kg/week) and high-dose (≥ 1 μg/kg/week)). RESULTS: Baseline characteristics were similar between groups; however, hemoglobin was lower among participants on high-dose (1.4 μg/kg/week) vs usual-dose (0.5 μg/kg/week) ESA.In adjusted analyses, high-dose ESA was associated with an increased odds for elevations in c-reactive protein and interleukin-6 (p < 0.05 for both). There was no correlation between high-dose ESA and adipokines. Higher ESA dose correlated with higher levels of sEpoR (rs = 0.39, p = 0.03). In adjusted analyses, higher ESA dose (per μcg/kg/week) was associated with a 53% greater odds of sEpoR being above the median (p < 0.05). CONCLUSION: High-dose ESA requirement among anemic CKD participants was associated with elevated inflammatory biomarkers and higher levels of circulating sEpoR, an inhibitor of erythropoiesis. Further research confirming these findings is warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT00526747.

Authors
Inrig, JK; Bryskin, SK; Patel, UD; Arcasoy, M; Szczech, LA
MLA Citation
Inrig, JK, Bryskin, SK, Patel, UD, Arcasoy, M, and Szczech, LA. "Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors. (Published online)" BMC Nephrol 12 (December 12, 2011): 67-.
PMID
22152013
Source
pubmed
Published In
BMC Nephrology
Volume
12
Publish Date
2011
Start Page
67
DOI
10.1186/1471-2369-12-67

Erythropoietin for oncology supportive care.

Recombinant human erythropoietin (rhEPO), the prototype erythropoiesis-stimulating agent developed in the 1980s, was among the first recombinant human proteins to be marketed for clinical use in the oncology setting. Anemia is a frequent concern in patients with cancer receiving myelosuppressive chemotherapy and the availability of rhEPO as an alternative to red blood cell transfusions to treat symptomatic anemia created excitement among clinicians, particularly during an era of mounting concern for transfusion-transmissible infections. Early studies of rhEPO for chemotherapy-induced anemia in patients with non-myeloid malignancies showed these agents improved hemoglobin levels and reduced transfusion rates. rhEPO therapy was reported to decrease fatigue and improve quality of life, although the magnitude and clinical meaningfulness of these effects have been debated. More recent clinical trials since 2003 linking rhEPO therapy to increased risk of tumor progression, thrombo-vascular events and mortality prompted implementation of use restrictions to minimize potential for harm. Scientific research to understand the basic mechanisms of the biologic effects of erythropoietin at the cellular receptor and signaling level has revealed pleiotropic cytokine effects extending beyond erythropoiesis regulation. The importance of erythropoietin receptor signaling in normal, non-erythroid tissues and in pre-clinical tumor models has been under intense investigation and scrutiny, as potential mechanisms of the adverse outcomes associated with rhEPO therapy have been debated. Further research will be required to clarify the complex interplay between the diverse hematopoietic and non-hematopoietic effects of erythropoietin in normal and malignant tissues and to optimize the clinical use of rhEPO in the supportive care of cancer patients.

Authors
McKinney, M; Arcasoy, MO
MLA Citation
McKinney, M, and Arcasoy, MO. "Erythropoietin for oncology supportive care." Experimental cell research 317.9 (May 2011): 1246-1254. (Review)
PMID
21396935
Source
epmc
Published In
Experimental Cell Research
Volume
317
Issue
9
Publish Date
2011
Start Page
1246
End Page
1254
DOI
10.1016/j.yexcr.2011.03.003

American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.

PURPOSE: To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

Authors
Rizzo, JD; Brouwers, M; Hurley, P; Seidenfeld, J; Arcasoy, MO; Spivak, JL; Bennett, CL; Bohlius, J; Evanchuk, D; Goode, MJ; Jakubowski, AA; Regan, DH; Somerfield, MR; American Society of Clinical Oncology, ; American Society of Hematology,
MLA Citation
Rizzo, JD, Brouwers, M, Hurley, P, Seidenfeld, J, Arcasoy, MO, Spivak, JL, Bennett, CL, Bohlius, J, Evanchuk, D, Goode, MJ, Jakubowski, AA, Regan, DH, Somerfield, MR, American Society of Clinical Oncology, , and American Society of Hematology, . "American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer." J Clin Oncol 28.33 (November 20, 2010): 4996-5010. (Review)
PMID
20975064
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
33
Publish Date
2010
Start Page
4996
End Page
5010
DOI
10.1200/JCO.2010.29.2201

American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.

PURPOSE: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

Authors
Rizzo, JD; Brouwers, M; Hurley, P; Seidenfeld, J; Arcasoy, MO; Spivak, JL; Bennett, CL; Bohlius, J; Evanchuk, D; Goode, MJ; Jakubowski, AA; Regan, DH; Somerfield, MR; American Society of Hematology and the American Society of Clinical Oncology Practice Guideline Update Committee,
MLA Citation
Rizzo, JD, Brouwers, M, Hurley, P, Seidenfeld, J, Arcasoy, MO, Spivak, JL, Bennett, CL, Bohlius, J, Evanchuk, D, Goode, MJ, Jakubowski, AA, Regan, DH, Somerfield, MR, and American Society of Hematology and the American Society of Clinical Oncology Practice Guideline Update Committee, . "American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer." Blood 116.20 (November 18, 2010): 4045-4059. (Review)
PMID
20974674
Source
pubmed
Published In
Blood
Volume
116
Issue
20
Publish Date
2010
Start Page
4045
End Page
4059
DOI
10.1182/blood-2010-08-300541

Non-erythroid effects of erythropoietin.

Authors
Arcasoy, MO
MLA Citation
Arcasoy, MO. "Non-erythroid effects of erythropoietin." Haematologica 95.11 (November 2010): 1803-1805.
PMID
21037325
Source
pubmed
Published In
Haematologica
Volume
95
Issue
11
Publish Date
2010
Start Page
1803
End Page
1805
DOI
10.3324/haematol.2010.030213

Unraveling a sticky paradox.

Authors
Kransdorf, EP; Arcasoy, MO
MLA Citation
Kransdorf, EP, and Arcasoy, MO. "Unraveling a sticky paradox." Am J Med 123.5 (May 2010): 417-419.
PMID
20399316
Source
pubmed
Published In
American Journal of Medicine
Volume
123
Issue
5
Publish Date
2010
Start Page
417
End Page
419
DOI
10.1016/j.amjmed.2010.01.003

Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation.

OBJECTIVE: Polycythemia vera (PV) is characterized by erythrocytosis associated with the presence of the activating JAK2(V617F) mutation in a variable proportion of hematopoietic cells. JAK2(V617F) is detected in other myeloproliferative neoplasms, does not appear to be the PV-initiating event, and its specific role in deregulated erythropoiesis in PV is incompletely understood. We investigated the pathogenesis of PV to characterize abnormal proliferation and apoptosis responses and aberrant oncogenic pathway activation in primary PV erythroid precursors. MATERIALS AND METHODS: Peripheral blood CD34(+) cells isolated from PV patients and healthy controls were grown in liquid culture to expand a population of primary erythroblasts for experiments designed to analyze cellular proliferation, apoptosis, JAK2(V617F) mutation status, cytokine-dependent protein phosphorylation and gene expression profiling using Affymetrix microarrays. RESULTS: The survival and proliferation of PV erythroblasts were growth factor-dependent under strict serum-free conditions requiring both erythropoietin (EPO) and stem cell factor. PV erythroblasts exhibited EPO hypersensitivity and enhanced cellular proliferation associated with increased EPO-mediated extracellular signal-regulated kinases 1 and 2 phosphorylation. EPO-induced AKT phosphorylation was observed in PV but not normal erythroblasts, an effect associated with apoptosis resistance in PV erythroblasts. Analysis of gene expression and oncogenic pathway activation signatures revealed increased RAS (p<0.01) and phosphoinositide-3 kinase (p<0.05) pathway activation in PV erythroblasts. CONCLUSION: Deregulated erythropoiesis in PV involves EPO hypersensitivity and apoptosis resistance of erythroid precursor cells associated with abnormally increased activation of RAS-ERK and phosphoinositide-3 kinase-AKT pathways. These data suggest that investigation of the mechanisms of abnormal RAS and phosphoinositide-3 kinase pathway activation in erythroblasts may contribute to our understanding of the molecular pathogenesis of PV.

Authors
Laubach, JP; Fu, P; Jiang, X; Salter, KH; Potti, A; Arcasoy, MO
MLA Citation
Laubach, JP, Fu, P, Jiang, X, Salter, KH, Potti, A, and Arcasoy, MO. "Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation." Exp Hematol 37.12 (December 2009): 1411-1422.
PMID
19815050
Source
pubmed
Published In
Experimental Hematology
Volume
37
Issue
12
Publish Date
2009
Start Page
1411
End Page
1422
DOI
10.1016/j.exphem.2009.09.009

Constitutively active erythropoietin receptor expression in breast cancer cells promotes cellular proliferation and migration through a MAP-kinase dependent pathway.

The role of erythropoietin receptor (EpoR) expression in tumor cells and the potential of EpoR-mediated signaling to contribute to cellular proliferation and invasiveness require further characterization. To determine whether EpoR expression and activation in tumor cells modulates intracellular signal transduction to promote cellular proliferation and migration, we employed a novel experimental model using human breast cancer cells engineered to stably express a constitutively active EpoR-R129C variant. EpoR-R129C expression resulted in increased cellular proliferation and migration of breast cancer cells and these effects were associated with significantly increased Epo-induced phosphorylation of ERK1/2, AKT and c-Jun-NH2-kinase (SAPK/JNK) proteins. Expression of the constitutively active EpoR-R129C receptor promoted the proliferation and migration of breast cancer cells via activation of ERK- and SAPK/JNK-dependent signaling pathways, respectively. These findings suggest that EpoR over-expression and activation in breast cancer cells has the potential to contribute to tumor progression by promoting the proliferation and invasiveness of the neoplastic cells.

Authors
Fu, P; Jiang, X; Arcasoy, MO
MLA Citation
Fu, P, Jiang, X, and Arcasoy, MO. "Constitutively active erythropoietin receptor expression in breast cancer cells promotes cellular proliferation and migration through a MAP-kinase dependent pathway." Biochem Biophys Res Commun 379.3 (February 13, 2009): 696-701.
PMID
19133231
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
379
Issue
3
Publish Date
2009
Start Page
696
End Page
701
DOI
10.1016/j.bbrc.2008.12.146

Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.

Erythroid Krüppel-like factor (EKLF) is a Krüppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells. EKLF-deficient (Eklf(-/-)) mice die at day 14.5 of gestation from severe anemia. In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differentiation in Eklf(-/-) embryos. To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild-type and Eklf(-/-) early erythroid progenitor cells. These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub. E2f2 mRNA and protein levels were markedly decreased in Eklf(-/-) early erythroid progenitor cells, which showed a delay in the G(1)-to-S-phase transition. Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo. Consistent with the role of EKLF as a chromatin modifier, EKLF binding sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells. We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.

Authors
Pilon, AM; Arcasoy, MO; Dressman, HK; Vayda, SE; Maksimova, YD; Sangerman, JI; Gallagher, PG; Bodine, DM
MLA Citation
Pilon, AM, Arcasoy, MO, Dressman, HK, Vayda, SE, Maksimova, YD, Sangerman, JI, Gallagher, PG, and Bodine, DM. "Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2." Mol Cell Biol 28.24 (December 2008): 7394-7401.
PMID
18852285
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
28
Issue
24
Publish Date
2008
Start Page
7394
End Page
7401
DOI
10.1128/MCB.01087-08

Erythropoiesis-stimulating agent use in cancer: preclinical and clinical perspectives.

Erythropoiesis-stimulating agents (ESA) used for the treatment of chemotherapy-induced anemia in cancer patients have been associated with adverse outcomes of enhanced tumor progression and impaired survival in a series of recent clinical trials. As clinical practice guidelines for ESA administration in cancer patients have evolved to improve safety, the mechanisms underlying the adverse outcomes and whether ESAs exert direct and/or indirect effects in primary tumors to modulate tumor cell growth, survival, and chemoradiotherapy responses remain uncertain. Erythropoietin receptor (EpoR) expression in tumor cells has raised the simplistic possibility that Epo signaling mediated via a functional cellular receptor may contribute to tumor progression in a direct manner. However, Epo biology in cancer is likely to be complex and an interplay of multiple factors is potentially involved in the overall tumor response to exogenous Epo. Optimization of ESA use as an important supportive therapy modality in cancer patients, and further investigation of the role of Epo-EpoR in cancer biology will require a combination of carefully designed preclinical and clinical studies designed to ascertain not only the effect of ESA therapy on clinical outcomes such as tumor response, progression-free, and overall survival but also to investigate the potential effects of Epo on biomarkers of EpoR activation and factors related to tumor biology and chemoradiation responsiveness.

Authors
Arcasoy, MO
MLA Citation
Arcasoy, MO. "Erythropoiesis-stimulating agent use in cancer: preclinical and clinical perspectives." Clin Cancer Res 14.15 (August 1, 2008): 4685-4690. (Review)
PMID
18676735
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
15
Publish Date
2008
Start Page
4685
End Page
4690
DOI
10.1158/1078-0432.CCR-08-0264

Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation.

BACKGROUND AND OBJECTIVE: Internet-based disease management programs have the potential to improve patient care. The objective of this study was to determine whether an interactive, internet-based system enabling supervised, patient self-management of oral anticoagulant therapy provided management comparable to an established anticoagulation clinic. PATIENTS/METHODS: Sixty patients receiving chronic oral anticoagulant therapy who had access to the internet and a printer, were enrolled into this prospective, single-group, before-after study from a single clinic and managed between March 2002 and January 2003. Patients learned how to use a home prothrombin time monitor and how to access the system through the internet. Patients used the system for six months, with daily review by the supervising physician. The primary outcome variable was the difference in time in therapeutic range prior to and following introduction of internet-supervised patient self-management. RESULTS: The mean time in therapeutic range increased from 63% in the anticoagulation clinic (control period) to 74.4% during internet-supervised patient self-management (study period). The mean difference score between control and study periods was 11.4% (P = 0.004, 95% confidence interval 5.5-17.3%). There were no hemorrhagic or thromboembolic complications. CONCLUSIONS: This novel approach of internet-supervised patient self-management improved time in therapeutic range compared to an anticoagulation clinic. This is the first demonstration of an internet-based expert system enabling remote and effective management of patients on oral anticoagulants. Expert systems may be applicable for management of other chronic diseases.

Authors
O'Shea, SI; Arcasoy, MO; Samsa, G; Cummings, SE; Thames, EH; Surwit, RS; Ortel, TL
MLA Citation
O'Shea, SI, Arcasoy, MO, Samsa, G, Cummings, SE, Thames, EH, Surwit, RS, and Ortel, TL. "Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation." J Thromb Thrombolysis 26.1 (August 2008): 14-21.
PMID
17616845
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
26
Issue
1
Publish Date
2008
Start Page
14
End Page
21
DOI
10.1007/s11239-007-0068-y

Erythropoiesis-stimulating agents in cancer.

Authors
Arcasoy, MO
MLA Citation
Arcasoy, MO. "Erythropoiesis-stimulating agents in cancer." J Clin Oncol 26.18 (June 20, 2008): 3097-3098. (Letter)
PMID
18565902
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
18
Publish Date
2008
Start Page
3097
End Page
3098
DOI
10.1200/JCO.2008.16.0531

The non-haematopoietic biological effects of erythropoietin.

In the haematopoietic system, the principal function of erythropoietin (Epo) is the regulation of red blood cell production, mediated by its specific cell surface receptor (EpoR). Following the cloning of the Epo gene (EPO) and characterization of the selective haematopoietic action of Epo in erythroid lineage cells, recombinant Epo forms (epoetin-alfa, epoetin-beta and the long-acting analogue darbepoetin-alfa) have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients. Ubiquitous EpoR expression in non-erythroid cells has been associated with the discovery of diverse biological functions for Epo in non-haematopoietic tissues. During development, Epo-EpoR signalling is required not only for fetal liver erythropoiesis, but also for embryonic angiogenesis and brain development. A series of recent studies suggest that endogenous Epo-EpoR signalling contributes to wound healing responses, physiological and pathological angiogenesis, and the body's innate response to injury in the brain and heart. Epo and its novel derivatives have emerged as major tissue-protective cytokines that are being investigated in the first human studies involving neurological and cardiovascular diseases. This review focuses on the scientific evidence documenting the biological effects of Epo in non-haematopoietic tissues and discusses potential future applications of Epo and its derivatives in the clinic.

Authors
Arcasoy, MO
MLA Citation
Arcasoy, MO. "The non-haematopoietic biological effects of erythropoietin." Br J Haematol 141.1 (April 2008): 14-31. (Review)
PMID
18324962
Source
pubmed
Published In
British Journal of Haematology
Volume
141
Issue
1
Publish Date
2008
Start Page
14
End Page
31
DOI
10.1111/j.1365-2141.2008.07014.x

Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody) with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.

Authors
Hardee, ME; Cao, Y; Fu, P; Jiang, X; Zhao, Y; Rabbani, ZN; Vujaskovic, Z; Dewhirst, MW; Arcasoy, MO
MLA Citation
Hardee, ME, Cao, Y, Fu, P, Jiang, X, Zhao, Y, Rabbani, ZN, Vujaskovic, Z, Dewhirst, MW, and Arcasoy, MO. "Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. (Published online)" PLoS One 2.6 (June 20, 2007): e549-.
PMID
17579721
Source
pubmed
Published In
PloS one
Volume
2
Issue
6
Publish Date
2007
Start Page
e549
DOI
10.1371/journal.pone.0000549

Aplastic anaemia as an autoimmune complication of thymoma.

Authors
Arcasoy, MO; Gockerman, JP
MLA Citation
Arcasoy, MO, and Gockerman, JP. "Aplastic anaemia as an autoimmune complication of thymoma." Br J Haematol 137.4 (May 2007): 272-.
PMID
17355260
Source
pubmed
Published In
British Journal of Haematology
Volume
137
Issue
4
Publish Date
2007
Start Page
272
DOI
10.1111/j.1365-2141.2007.06523.x

Erythropoietin protects cardiac myocytes against anthracycline-induced apoptosis.

The cardiotoxic adverse effects of anthracycline antibiotics limit their therapeutic utility as essential components of chemotherapy regimens for hematologic and solid malignancies. Here we show that the hematopoietic cytokine erythropoietin attenuates doxorubicin-induced apoptosis of primary neonatal rat ventricular cardiomyocytes in a dose-dependent manner. Erythropoietin treatment induced rapid, time-dependent phosphorylation of MAP kinases (MAPK) Erk1/2 and the phosphatidylinositol 3-kinase substrate Akt. Treatment of cardiomyocytes with inhibitors of phosphatidylinositol 3-kinase (LY294002) or Akt (Akti-1/2) abolished the protective effect of erythropoietin, whereas treatment with MAPK kinase (MEK1) inhibitor U0126 did not. Erythropoietin also induced the phosphorylation of GSK-3beta, a downstream target of PI3K-Akt. Because phosphorylation is known to inactivate GSK-3beta, we investigated whether GSK-3beta inhibition is cardioprotective. We found that GSK-3beta inhibitors SB216763 or lithium chloride blocked doxorubicin-induced cardiomyocyte apoptosis in a manner similar to erythropoietin, suggesting that GSK-3beta inhibition is involved in erythropoietin-mediated cardioprotection. Erythropoietin may serve as a novel cardioprotective agent against anthracycline-induced cardiotoxicity.

Authors
Fu, P; Arcasoy, MO
MLA Citation
Fu, P, and Arcasoy, MO. "Erythropoietin protects cardiac myocytes against anthracycline-induced apoptosis." Biochem Biophys Res Commun 354.2 (March 9, 2007): 372-378.
PMID
17250809
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
354
Issue
2
Publish Date
2007
Start Page
372
End Page
378
DOI
10.1016/j.bbrc.2007.01.044

Deferasirox versus deferoxamine.

Authors
Martin, MG; Arcasoy, MO
MLA Citation
Martin, MG, and Arcasoy, MO. "Deferasirox versus deferoxamine." Blood 108.2 (July 15, 2006): 774-775. (Letter)
PMID
16822908
Source
pubmed
Published In
Blood
Volume
108
Issue
2
Publish Date
2006
Start Page
774
End Page
775
DOI
10.1182/blood-2006-02-002436

Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.

Evidence for erythropoietin signaling has been shown in several nonhematopoietic tissues, including many tumor types. Clinically, recombinant erythropoietin treatment of malignancy-related anemia has yet to be definitively associated with any modulation of chemotherapy or radiotherapy efficacy. Preclinically, recombinant erythropoietin has been shown to increase tumor oxygenation, but the direct effects of recombinant erythropoietin on tumor cells that express erythropoietin receptor are not yet fully characterized. This study examined the effects of exogenous recombinant erythropoietin on rodent mammary adenocarcinoma cells (R3230) in vitro and in vivo, and determined the effects of systemic recombinant erythropoietin on tumor growth delay in Taxol treatment. We showed that systemic recombinant erythropoietin treatment of rats bearing R3230 mammary carcinomas induced an increase in phospho-Akt levels within tumor cells. This was associated with a decrease in the frequency of apoptotic cells in tumors from recombinant erythropoietin-treated animals, but did not noticeably affect tumor growth rate. In vitro studies revealed that not only does recombinant erythropoietin induce Akt phosphorylation, but it also stimulates phosphorylation of p44/42 mitogen-activated protein kinases, Erk1 and Erk2. Activation of erythropoietin-mediated signaling in R3230 cells was associated with dose-dependent inhibition of apoptosis in response to Taxol treatment and serum starvation, an effect that was blocked by the addition of a phosphatidylinositol-3-kinase inhibitor. Despite its cytoprotective effects in vitro, recombinant erythropoietin did not significantly affect tumor growth delay in Taxol treatment. This study shows direct recombinant erythropoietin-mediated activation of specific intracellular signaling pathways in mammary adenocarcinoma cells in vivo and in vitro. Modulation of tumor apoptosis pathways by recombinant erythropoietin may have negative consequences by decreasing the chemosensitivity and radiosensitivity of erythropoietin receptor-positive breast tumors, although it did not have any obvious effects on growth with or without chemotherapy in this model.

Authors
Hardee, ME; Rabbani, ZN; Arcasoy, MO; Kirkpatrick, JP; Vujaskovic, Z; Dewhirst, MW; Blackwell, KL
MLA Citation
Hardee, ME, Rabbani, ZN, Arcasoy, MO, Kirkpatrick, JP, Vujaskovic, Z, Dewhirst, MW, and Blackwell, KL. "Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity." Mol Cancer Ther 5.2 (February 2006): 356-361.
PMID
16505109
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
5
Issue
2
Publish Date
2006
Start Page
356
End Page
361
DOI
10.1158/1535-7163.MCT-05-0196

Erythropoietin biology in cancer.

Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation along the erythroid lineage. Recent studies have shown that Epo is a pleiotropic cytokine that is proangiogenic and exerts broad tissue-protective effects in diverse nonhematopoietic organs. Recombinant Epo (rEpo) has been widely used in the clinic to prevent or treat malignancy-associated anemia. A series of clinical trials have documented the efficacy of rEpo in reducing RBC transfusion requirements and improving quality of life in cancer patients, and a recent meta-analysis suggested a positive effect on survival. However, two randomized trials reported negative outcomes with rEpo, as patients in the rEpo arm fared worse than their placebo-treated counterparts with respect to progression-free survival. The expression of Epo receptor (EpoR) in cancer cells has raised the possibility that exogenous rEpo may exert direct effects on tumor cells associated with the potential for stimulation of proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiation therapy. The presence of an autocrine-paracrine Epo-EpoR system in tumors and potential effects of Epo on tumor microenvironment and angiogenesis are consistent with a complex biology for Epo-EpoR signaling in cancer that requires further research. This review describes Epo and EpoR biology, focusing on the pleiotropic effects of Epo on nonhematopoietic tissues as well as the expression and function of EpoR in cancer cells.

Authors
Hardee, ME; Arcasoy, MO; Blackwell, KL; Kirkpatrick, JP; Dewhirst, MW
MLA Citation
Hardee, ME, Arcasoy, MO, Blackwell, KL, Kirkpatrick, JP, and Dewhirst, MW. "Erythropoietin biology in cancer." Clin Cancer Res 12.2 (January 15, 2006): 332-339. (Review)
PMID
16428469
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
2
Publish Date
2006
Start Page
332
End Page
339
DOI
10.1158/1078-0432.CCR-05-1771

Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling.

Langendorff-perfused rat hearts treated with EPO exhibited significantly improved postischemic recovery of left ventricular developed pressure (LVDP) and reduced infarct size compared with control hearts. Perfusion with the mitogen/extracellular signal-regulated kinase (MEK) inhibitor U0126 just before and concomitant with EPO treatment abolished EPO-induced phosphorylation of the MEK substrate extracellular signal-regulated kinase (ERK) but had no effect of EPO-mediated cardioprotection. EPO treatment of the perfused hearts induced translocation of protein kinase C (PKC) epsilon isoform to the membrane fraction of the hearts and the protective effect of EPO was significantly inhibited by the PKC catalytic inhibitor chelerythrine added before and concomitant with EPO. These data demonstrate that EPO-mediated activation of the PKC signaling pathway before or during ischemia is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. Perfusion with the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin just before and concomitant with EPO treatment attenuated EPO-induced phosphorylation of the PI3K substrate Akt but had no effect on EPO-mediated cardioprotection. However, when wortmannin was added during EPO treatment and continued during reperfusion, EPO-mediated cardioprotection was significantly inhibited. We also show that postischemia EPO treatment at the onset of reperfusion significantly improved recovery of LVDP and reduced infarct size. Postischemia cardioprotection by EPO required the PI3K pathway but was not affected by inhibition of PKC at the time of EPO treatment.

Authors
Hanlon, PR; Fu, P; Wright, GL; Steenbergen, C; Arcasoy, MO; Murphy, E
MLA Citation
Hanlon, PR, Fu, P, Wright, GL, Steenbergen, C, Arcasoy, MO, and Murphy, E. "Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling." FASEB J 19.10 (August 2005): 1323-1325.
PMID
15946993
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
19
Issue
10
Publish Date
2005
Start Page
1323
End Page
1325
DOI
10.1096/fj.04-3545fje

Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor.

The regeneration of circulating red blood cells in response to anaemia associated with blood loss or haemolysis involves an increased rate of erythropoiesis and expansion of proerythroblasts, the bone marrow precursor cells that terminally differentiate into mature erythrocytes. This study investigated the mechanisms by which erythropoietin (Epo) and stem cell factor (Scf) modulate the expansion of proerythroblasts. Homogenous populations of primary human proerythroblasts were generated in liquid cultures of CD34(+) cells. In serum-free cultures, proerythroblasts failed to survive in the presence of Epo or Scf alone, but exhibited synergistic proliferation in response to combined Epo and Scf treatment, exhibiting one-log expansion in 5 d. Intracellular signal transduction in response to Epo and Scf revealed that tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5, a downstream target for the non-receptor tyrosine kinase, Janus kinase 2 (Jak2), was mediated by Epo but not Scf. The mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) 1-2 were phosphorylated in response to either Epo or Scf. Phosphorylation of Akt, a signalling molecule downstream of phosphatidylinositol 3-kinase (PI3K), was observed following Scf but not Epo treatment. To determine the contribution of specific signalling pathways to synergistic expansion of proerythroblasts in response to co-operative effects of Epo and Scf, cells were treated with kinase inhibitors targeting Jak2, PI3K and MAPK kinase. There was a significant, dose-dependent inhibition of proerythroblast expansion in response to all three kinase inhibitors. In conclusion, Epo- and Scf-mediated co-operative, synergistic expansion of primary erythroid precursors requires selective activation of multiple signalling pathways, including the Jak-Stat, PI3K and MAPK pathways.

Authors
Arcasoy, MO; Jiang, X
MLA Citation
Arcasoy, MO, and Jiang, X. "Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor." Br J Haematol 130.1 (July 2005): 121-129.
PMID
15982354
Source
pubmed
Published In
British Journal of Haematology
Volume
130
Issue
1
Publish Date
2005
Start Page
121
End Page
129
DOI
10.1111/j.1365-2141.2005.05580.x

Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain.

Erythropoietin receptor (EPOR) gene mutations leading to truncations of the cytoplasmic, carboxy-terminal region of EPOR have been described in some patients with primary familial and congenital polycythemia (PFCP), a disorder characterized by isolated erythrocytosis and increased sensitivity of erythroid progenitors to Epo. We studied the role of EPOR in the pathogenesis of PFCP and the requirement for intracytoplasmic tyrosine residues Y285 and Y344 in generation of Epo hypersensitivity phenotype. Interleukin-3-dependent hematopoietic cells were engineered to express variant human EPORs using retrovirus-mediated gene transfer. We introduced tyrosine to phenylalanine substitutions in EPOR-ME, a naturally occurring, mutant human EPOR (G5881T), truncated by 110 carboxy-terminal amino acids and associated with autosomal dominantly inherited PFCP. Cells expressing EPOR-ME exhibited increased Epo sensitivity compared to cells expressing wild type EPOR. Mutation of Y285 alone had a relatively minor effect on Epo hypersensitivity whereas mutation of Y344 resulted in loss of increased Epo sensitivity. Expression of a tyrosine-null truncated EPOR conferred further decrease of Epo-mediated proliferation suggesting that both Y285 and Y344 may contribute to proliferation signals. In the context of EPOR-ME, Y344 was required for Epo-induced Stat5 tyrosine phosphorylation. The positive effect of either Y285 or Y344 on cellular proliferation was associated with Epo-induced tyrosine phosphorylation of Stat1. These findings suggest that both tyrosine residues Y285 and Y344 in the cytoplasmic domain of EPOR-ME may contribute to increased Epo sensitivity that is characteristic of PFCP phenotype.

Authors
Arcasoy, MO; Karayal, AF
MLA Citation
Arcasoy, MO, and Karayal, AF. "Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain." Biochim Biophys Acta 1740.1 (April 15, 2005): 17-28.
PMID
15878737
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1740
Issue
1
Publish Date
2005
Start Page
17
End Page
28
DOI
10.1016/j.bbadis.2005.03.003

Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells.

OBJECTIVE: In a previous study, we showed that activation of a transfected human erythropoietin receptor (EPOR) in the murine myeloid cell line 32D resulted in the development of morphologic features of granulocytic differentiation and expression of the neutrophil primary granule protein myeloperoxidase. We now studied if EPOR signaling could also mediate secondary granule protein gene expression and investigated the signal transduction requirements for induction of secondary granule gene expression in 32D cells. MATERIALS AND METHODS: Wild-type and variant 32D cells expressing normal or chimeric EPORs or receptors for granulocyte colony-stimulating factor (G-CSFRs) were stimulated with EPO or G-CSF and the expression of granulocyte-specific genes was analyzed by Northern blot analysis. To determine the signaling mechanisms required for secondary granule protein gene induction, the activation of STAT pathways following growth factor stimulation was studied by Western blot analysis. RESULTS: We found that EPO treatment of 32D cells engineered to express EPOR did not result in induction of the secondary granule protein genes encoding lactoferrin and 24p3 lipocalin, the mouse homolog of human N-Gal, or the myeloid transcription factor C/EBPepsilon. Replacement of the intracellular domain of EPOR with the intracellular domain of G-CSFR in a chimeric receptor was associated with EPO-mediated induction of lactoferrin, 24p3 lipocalin, and C/EBPepsilon genes. We found that STAT3 phosphorylation was mediated by the intracellular domain of G-CSFR, but not EPOR. Replacement of one or two of the STAT5 binding sites in the intracytoplasmic domain of the EPOR with STAT3 binding sites resulted in EPO-mediated STAT3 activation and a marked increase in the expression of the 24p3 lipocalin gene. Knockdown of STAT3 protein levels with siRNA caused significant decrease in 24p3 lipocalin gene induction. CONCLUSION: These results indicate that EPOR signaling cannot substitute for G-CSFR signaling to stimulate secondary granule protein gene expression in 32D cells. In addition, STAT3 is a critical mediator of 24p3 lipocalin gene expression in these cells.

Authors
Wang, L; Arcasoy, MO; Watowich, SS; Forget, BG
MLA Citation
Wang, L, Arcasoy, MO, Watowich, SS, and Forget, BG. "Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells." Exp Hematol 33.3 (March 2005): 308-317.
PMID
15730854
Source
pubmed
Published In
Experimental Hematology
Volume
33
Issue
3
Publish Date
2005
Start Page
308
End Page
317
DOI
10.1016/j.exphem.2004.11.014

Erythropoietin and erythropoietin receptor expression in human prostate cancer.

Erythropoietin is a hematopoietic cytokine that regulates the production of red blood cells. Erythropoietin is normally produced in the adult kidney in a hypoxia-inducible manner. The recombinant form of human erythropoietin is in clinical use for the prevention and treatment of anemia that is associated with cancer and its treatment with chemoradiation therapy. A series of recent studies from our laboratory and others have reported the expression of receptors for erythropoietin in several different types of human cancer cells. In the present study, we investigated the expression of erythropoietin receptor and its ligand erythropoietin in human prostate cancer. In clinical specimens of prostate cancer, we found abundant expression of erythropoietin receptor protein in all primary tumors examined using immunohistochemistry. Furthermore, we observed erythropoietin coexpression in prostate cancer cells by immunohistochemical analysis. To determine whether monolayer cultures of continuous cell lines derived from prostate cancer also express erythropoietin receptor and erythropoietin, we studied well-characterized hormone-responsive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines. We performed reverse-transcription and polymerase chain reaction assays to detect erythropoietin receptor and erythropoietin mRNA transcripts, and also immunoprecipitation and immunoblotting to detect erythropoietin receptor protein expression in prostate cancer cells. These experiments revealed the expression of both erythropoietin receptor and erythropoietin in LNCaP and PC-3 cells suggesting that these prostate cancer cell lines may serve as useful experimental models for further studies of erythropoietin and erythropoietin receptor function in prostate cancer. The coexpression of erythropoietin receptor and its ligand erythropoietin in human prostate cancer cells suggests the potential for growth regulation by erythropoietin-erythropoietin receptor in an autocrine or paracrine manner.

Authors
Arcasoy, MO; Amin, K; Vollmer, RT; Jiang, X; Demark-Wahnefried, W; Haroon, ZA
MLA Citation
Arcasoy, MO, Amin, K, Vollmer, RT, Jiang, X, Demark-Wahnefried, W, and Haroon, ZA. "Erythropoietin and erythropoietin receptor expression in human prostate cancer." Mod Pathol 18.3 (March 2005): 421-430.
PMID
15467711
Source
pubmed
Published In
Modern Pathology
Volume
18
Issue
3
Publish Date
2005
Start Page
421
End Page
430
DOI
10.1038/modpathol.3800288

T-cell-mediated pure red-cell aplasia in systemic lupus erythematosus: response to cyclosporin A and mycophenolate mofetil.

Authors
Arcasoy, MO; Chao, NJ
MLA Citation
Arcasoy, MO, and Chao, NJ. "T-cell-mediated pure red-cell aplasia in systemic lupus erythematosus: response to cyclosporin A and mycophenolate mofetil." Am J Hematol 78.2 (February 2005): 161-163. (Letter)
PMID
15682416
Source
pubmed
Published In
American Journal of Hematology
Volume
78
Issue
2
Publish Date
2005
Start Page
161
End Page
163
DOI
10.1002/ajh.20237

Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia.

PURPOSE: Erythropoietin, an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor [erythropoietin receptor (EPOR)]. The recombinant form of human erythropoietin is used to prevent or treat anemia in cancer patients. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, erythropoietin treatment was associated with poorer locoregional progression-free survival. The purpose of our study was to determine whether EPOR and its ligand erythropoietin are expressed in primary head and neck cancer. We also investigated the hypothesis that erythropoietin expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness, and poor prognosis. EXPERIMENTAL DESIGN: Twenty-one patients received an i.v. infusion of the hypoxia marker pimonidazole hydrochloride before multiple tumor biopsies. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding. RESULTS: EPOR expression was present in tumor cells in 97% of the biopsies. Coexpression of erythropoietin was observed in 90% of biopsies. Erythropoietin and pimonidazole adduct staining did not always colocalize within tumors, but there was a significant positive correlation between levels of microregional erythropoietin expression and pimonidazole binding. CONCLUSIONS: The coexpression of erythropoietin and EPOR in tumor cells suggests that erythropoietin may potentially function as an autocrine or paracrine factor in head and neck cancer. The expression of the hypoxia-inducible protein erythropoietin in tumor cells correlates with levels of tumor hypoxia.

Authors
Arcasoy, MO; Amin, K; Chou, S-C; Haroon, ZA; Varia, M; Raleigh, JA
MLA Citation
Arcasoy, MO, Amin, K, Chou, S-C, Haroon, ZA, Varia, M, and Raleigh, JA. "Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia." Clin Cancer Res 11.1 (January 1, 2005): 20-27.
PMID
15671524
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
1
Publish Date
2005
Start Page
20
End Page
27

Pure red cell aplasia following pegylated interferon alpha treatment.

Authors
Arcasoy, MO; Rockey, DC; Heneghan, MA
MLA Citation
Arcasoy, MO, Rockey, DC, and Heneghan, MA. "Pure red cell aplasia following pegylated interferon alpha treatment." Am J Med 117.8 (October 15, 2004): 619-620. (Letter)
PMID
15465516
Source
pubmed
Published In
The American Journal of Medicine
Volume
117
Issue
8
Publish Date
2004
Start Page
619
End Page
620
DOI
10.1016/j.amjmed.2004.04.023

Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury.

Erythropoietin (EPO), the principal hematopoietic cytokine that regulates mammalian erythropoiesis, exhibits diverse cellular effects in non-hematopoietic tissues. The physiologic functions of EPO are mediated by its specific cell-surface receptor EPOR. In this study, we demonstrate EPOR expression in adult rat cardiac myocytes and examine the direct effects of EPO on the heart to investigate whether recombinant EPO may exert an acute cardioprotective effect during ischemia-reperfusion injury. To determine whether EPO is cardioprotective, isolated rat hearts were perfused for 10 min in the Langendorff-mode with Krebs-Henseleit buffer in the absence or presence of brief recombinant EPO treatment while left-ventricular-developed pressure (LVDP) was measured continuously to assess contractile function. The hearts were then subjected to 20 min of normothermic global ischemia followed by 25 min of reperfusion. The post-ischemic recovery of LVDP in the untreated control hearts was 26 +/- 5% of their baseline LVDP, whereas hearts pretreated with EPO exhibited significantly improved post-ischemic recovery to 57 +/- 7%. We used 31P nuclear magnetic resonance (NMR) spectroscopy to determine whether modulation of intracellular pH and/or high-energy phosphate levels during ischemia contributed to EPO-mediated cardioprotection. These experiments revealed that the rapid cardioprotective effect of EPO during ischemia-reperfusion injury was associated with preservation of ATP levels in the ischemic myocardium.

Authors
Wright, GL; Hanlon, P; Amin, K; Steenbergen, C; Murphy, E; Arcasoy, MO
MLA Citation
Wright, GL, Hanlon, P, Amin, K, Steenbergen, C, Murphy, E, and Arcasoy, MO. "Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury." FASEB J 18.9 (June 2004): 1031-1033.
PMID
15059965
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
18
Issue
9
Publish Date
2004
Start Page
1031
End Page
1033
DOI
10.1096/fj.03-1289fje

Iron overload due to X-linked sideroblastic anemia in an African American man.

Authors
Collins, TS; Arcasoy, MO
MLA Citation
Collins, TS, and Arcasoy, MO. "Iron overload due to X-linked sideroblastic anemia in an African American man." Am J Med 116.7 (April 1, 2004): 501-502. (Letter)
PMID
15047047
Source
pubmed
Published In
The American Journal of Medicine
Volume
116
Issue
7
Publish Date
2004
Start Page
501
End Page
502
DOI
10.1016/j.amjmed.2003.10.032

A novel role for erythropoietin during fibrin-induced wound-healing response.

In this study, we investigated the role of the hematopoietic cytokine erythropoietin (EPO) during wound healing, the physiological response to tissue injury. We used an in vivo wound-healing assay (fibrin Z-chambers) consisting of fibrin-filled chambers implanted subcutaneously in rats. The fibrin inside the chambers is replaced by granulation tissue consisting of new blood vessels, macrophages and fibroblasts as part of the wound-healing response. Local, exogenous recombinant EPO administration into the fibrin matrix significantly increased granulation tissue formation in a dose-dependent manner. To investigate the physiological role of endogenous EPO during wound healing, we used soluble EPO receptor or anti-EPO monoclonal antibodies to neutralize EPO and observed dose-dependent inhibition of granulation tissue formation, consistent with an important role for EPO in the wound-healing cascade. The ability of recombinant EPO to promote wound healing was associated with a proangiogenic effect during granulation tissue formation. We also found abundant expression of EPO receptor protein in macrophages, cells that play a pivotal role during wound healing. Modulation of wound healing because of administration of recombinant EPO or inhibition of endogenous EPO-EPO receptor correlated with changes in levels of inducible nitric oxide synthase protein in granulation tissue. These data demonstrate a novel function for EPO by providing in vivo evidence for a physiological role during fibrin-induced wound healing.

Authors
Haroon, ZA; Amin, K; Jiang, X; Arcasoy, MO
MLA Citation
Haroon, ZA, Amin, K, Jiang, X, and Arcasoy, MO. "A novel role for erythropoietin during fibrin-induced wound-healing response." Am J Pathol 163.3 (September 2003): 993-1000.
PMID
12937140
Source
pubmed
Published In
The American journal of pathology
Volume
163
Issue
3
Publish Date
2003
Start Page
993
End Page
1000
DOI
10.1016/S0002-9440(10)63459-1

Expression of erythropoietin receptor splice variants in human cancer.

Erythropoietin (EPO) regulates mammalian erythropoiesis by binding to its transmembrane receptor EPOR. Recent studies demonstrated functional EPOR expression in human cancer cells. Recombinant human EPO was reported to stimulate the proliferation of monolayer cultures of breast and renal carcinoma cells. Furthermore, administration of EPO-EPOR antagonists delayed the growth of uterine, ovarian, and mammary carcinoma cells in experimental animal models. In this study, we show EPOR transcript and protein expression in breast, colon, lung, ovary, and prostate cancer cells. Using reverse transcription-polymerase chain reaction, we isolated and characterized several novel cDNAs for EPOR splice variants expressed in cancer cells. Deduced amino acid sequences of the cDNAs revealed splice variants encoding soluble EPOR or membrane-bound EPOR peptides with intra-cytoplasmic, carboxy-terminal truncations. These findings indicate the expression of multiple EPOR isoforms in human cancer cells that may modulate the cellular effects of recombinant human EPO or EPO-EPOR antagonists.

Authors
Arcasoy, MO; Jiang, X; Haroon, ZA
MLA Citation
Arcasoy, MO, Jiang, X, and Haroon, ZA. "Expression of erythropoietin receptor splice variants in human cancer." Biochem Biophys Res Commun 307.4 (August 8, 2003): 999-1007.
PMID
12878211
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
307
Issue
4
Publish Date
2003
Start Page
999
End Page
1007

Functional significance of erythropoietin receptor expression in breast cancer.

Erythropoietin (EPO) is the principal hematopoietic cytokine that regulates mammalian erythropoiesis by binding to its transmembrane receptor EpoR. Recent experimental evidence suggests that the biologic effects of EPO are not limited to the regulation of erythropoiesis. In studies focusing on nonhematopoietic effects of EpoR signaling, we found high levels of EpoR protein expression in human breast cancer cells. The purpose of the present study was to evaluate clinical breast cancer specimens for EPO and EpoR expression, characterize the relationship between EPO expression and tumor hypoxia in biopsies prelabeled with hypoxia marker pimonidazole, analyze breast cancer cell lines for EpoR expression, and study the functional significance of EpoR expression in breast cancer cells in vivo. Immunohistochemical analysis for EPO, EpoR expression, and pimonidazole adducts was performed on 26 tumor biopsies with contiguous sections from 10 patients with breast cancer. High levels of EpoR expression were found in cancer cells in 90% of tumors. EPO expression was found in 60% of tumors and EPO and EpoR colocalization in tumor cells was present in many cases. The expression pattern of EPO with respect to tumor hypoxia was variable, without consistent colocalization of EPO and hypoxia in tumor cells. Human and rat breast cancer tissue culture cells express EpoR mRNA and protein. To study the in vivo function of EpoR expression in breast cancer cells, we used rat syngeneic R3230Ac mammary adenocarcinoma cells in a tumor Z-chamber model (dual porous plexiglass chambers containing fibrin gel, cancer cells, and a putative anti-tumor compound implanted into the subcutaneous tissue of rats). Local, one-time administration of a neutralizing anti-EPO antibody, soluble EPO receptor, or an inhibitor of Jak2, a cytoplasmic tyrosine kinase essential for EPO-mediated mitogenesis, resulted in a delay in tumor growth with 45% reduction in maximal tumor depth in tumor Z-chambers in a dose-dependent manner. These studies demonstrate the expression of functional receptors for EPO in breast cancer cells.

Authors
Arcasoy, MO; Amin, K; Karayal, AF; Chou, S-C; Raleigh, JA; Varia, MA; Haroon, ZA
MLA Citation
Arcasoy, MO, Amin, K, Karayal, AF, Chou, S-C, Raleigh, JA, Varia, MA, and Haroon, ZA. "Functional significance of erythropoietin receptor expression in breast cancer." Lab Invest 82.7 (July 2002): 911-918.
PMID
12118093
Source
pubmed
Published In
Laboratory Investigation
Volume
82
Issue
7
Publish Date
2002
Start Page
911
End Page
918

Purification and characterization of the yeast-expressed erythropoietin mutant Epo (R103A), a specific inhibitor of human primary hematopoietic cell erythropoiesis.

A drug that specifically inhibits erythropoiesis would be clinically useful. The erythropoietin (Epo) mutant Epo (R103A) could potentially be used for this purpose. Epo (R103A) has a single amino acid substitution of alanine for arginine at position 103. Because of this mutation, Epo (R103A) is only able to bind to one of the 2 subunits of the erythropoietin receptor (EpoR) homodimer and is thus a competitive inhibitor of Epo activity. To produce large quantities of Epo (R103A) to test in animal models of thalassemia and sickle cell disease, we expressed and purified recombinant Epo (R103A) from the yeast Pichia pastoris. Using this method milligram quantities of highly purified Epo (R103A) are obtained. The yeast-expressed Epo (R103A) is properly processed and glycosylated and specifically inhibits Epo-dependent cell growth and (125)I-Epo binding. Epo (R103A) does not, however, directly induce apoptosis in 32D cells expressing EpoR. Epo (R103A) inhibits erythropoiesis of human CD34(+) hematopoietic cells and completely blocks erythroid burst-forming unit formation in normal human bone marrow colony assays. Yeast-expressed Epo (R103A) is a specific inhibitor of primary erythropoiesis suitable for testing in animal models.

Authors
Burns, S; Arcasoy, MO; Li, L; Kurian, E; Selander, K; Emanuel, PD; Harris, KW
MLA Citation
Burns, S, Arcasoy, MO, Li, L, Kurian, E, Selander, K, Emanuel, PD, and Harris, KW. "Purification and characterization of the yeast-expressed erythropoietin mutant Epo (R103A), a specific inhibitor of human primary hematopoietic cell erythropoiesis." Blood 99.12 (June 15, 2002): 4400-4405.
PMID
12036868
Source
pubmed
Published In
Blood
Volume
99
Issue
12
Publish Date
2002
Start Page
4400
End Page
4405

A novel mutation in the erythropoietin receptor gene is associated with familial erythrocytosis.

Primary familial erythrocytosis (familial polycythemia) is a rare myeloproliferative disorder with an autosomal dominant mode of inheritance. We studied a new kindred with autosomal dominantly inherited familial erythrocytosis. The molecular basis for the observed phenotype of isolated erythrocytosis is heterozygosity for a novel nonsense mutation affecting codon 399 in exon 8 of the erythropoietin receptor (EPOR) gene, encoding an EpoR peptide that is truncated by 110 amino acids at its C-terminus. The new EPOR gene mutation 5881G>T was found to segregate with isolated erythrocytosis in the affected family and this mutation represents the most extensive EpoR truncation reported to date, associated with familial erythrocytosis. Erythroid progenitors from an affected individual displayed Epo hypersensitivity in in vitro methylcellulose cultures, as indicated by more numerous erythroid burst-forming unit-derived colonies in low Epo concentrations compared to normal controls. Expression of mutant EpoR in interleukin 3-dependent hematopoietic cells was associated with Epo hyperresponsiveness compared to cells expressing wild-type EpoR.

Authors
Arcasoy, MO; Karayal, AF; Segal, HM; Sinning, JG; Forget, BG
MLA Citation
Arcasoy, MO, Karayal, AF, Segal, HM, Sinning, JG, and Forget, BG. "A novel mutation in the erythropoietin receptor gene is associated with familial erythrocytosis." Blood 99.8 (April 15, 2002): 3066-3069.
PMID
11929803
Source
pubmed
Published In
Blood
Volume
99
Issue
8
Publish Date
2002
Start Page
3066
End Page
3069

Erythropoietin mediates terminal granulocytic differentiation of committed myeloid cells with ectopic erythropoietin receptor expression.

OBJECTIVES: The precise role of hematopoietic cytokine/cytokine receptor interactions in lineage-restricted hematopoietic differentiation giving rise to mature blood cells of diverse function is incompletely defined. To study lineage-specific effects of cytokines during terminal hematopoietic differentiation, we examined the ability of erythropoietin (Epo) to mediate terminal granulocytic differentiation and induction of myeloid gene expression in committed myeloid cells, engineered to ectopically express Epo receptor (EpoR). METHODS: A cell culture model for granulocyte-macrophage colony stimulating factor (GM-CSF)-mediated granulocytic differentiation was used. EpoR was introduced by retrovirus-mediated gene transfer into multipotential, hematopoietic murine cell line EML, from which GM-CSF-responsive, promyelocytic EPRO cells were generated. In EPRO cells ectopically expressing EpoR, we examined the ability of Epo to mediate granulocytic differentiation and determined whether Epo-mediated neutrophil differentiation is associated with a pattern of myeloid gene expression comparable to that induced by GM-CSF. RESULTS: Studies of EpoR function in myeloid EPRO cells revealed that Epo/EpoR interaction can mediate terminal granulocytic differentiation of committed myeloid cells. In EPRO cells expressing EpoR, Epo-mediated neutrophil differentiation was associated with surface CD11b/CD18 (Mac-1) expression and induction of mRNA expression of specific myeloid genes including lactoferrin, gelatinase and C/EBPepsilon, in a manner similar to GM-CSF-mediated differentiation. CONCLUSIONS: These results indicate that Epo can deliver differentiative signals along a non-erythroid lineage, providing evidence for interchangeable cytokine receptor signals that mediate terminal differentiation of committed myeloid cells.

Authors
Arcasoy, MO; Maun, NA; Perez, L; Forget, BG; Berliner, N
MLA Citation
Arcasoy, MO, Maun, NA, Perez, L, Forget, BG, and Berliner, N. "Erythropoietin mediates terminal granulocytic differentiation of committed myeloid cells with ectopic erythropoietin receptor expression." Eur J Haematol 67.2 (August 2001): 77-87.
PMID
11722594
Source
pubmed
Published In
European Journal of Haematology
Volume
67
Issue
2
Publish Date
2001
Start Page
77
End Page
87

Familial polycythemia due to truncations of the erythropoietin receptor.

We studied a kindred with dominantly inherited familial erythrocytosis associated with heterozygosity for a deletion of seven nucleotides in exon 8 of the EpoR gene resulting in an EpoR peptide that is truncated by 59 amino acids in its C-terminal intracytoplasmic signal transduction domain. A seven basepair direct repeat sequence is present in the normal EpoR gene at the site of this mutation, consistent with the slipped mispairing model for the generation of short deletions during DNA replication. Hypersensitivity to erythropoietin of primary erythroid progenitors from an affected individual was observed in in vitro cultures of peripheral blood mononuclear cells, as indicated by the growth, at suboptimal concentrations of added Epo, of more numerous and larger BFU-E-derived erythroid cell colonies compared to those obtained from a normal control subject. To study mutant EpoR function, the cDNA encoding the mutant EpoR was stably transfected into murine growth factor (IL-3)-dependent 32D tissue culture cells. In proliferation assays, cells expressing the mutant EpoR displayed 5 to 10-fold increased sensitivity to Epo compared to cells expressing similar numbers of the wild type EpoR. In addition, the cells transfected with the mutant truncated receptor demonstrated prolonged activity of Jak2 kinase and Stat5 activity, molecules that mediate signal transduction by the EpoR.

Authors
Forget, BG; Degan, BA; Arcasoy, MO
MLA Citation
Forget, BG, Degan, BA, and Arcasoy, MO. "Familial polycythemia due to truncations of the erythropoietin receptor." Trans Am Clin Climatol Assoc 111 (2000): 38-44.
PMID
10881330
Source
pubmed
Published In
Transactions of the American Clinical and Climatological Association
Volume
111
Publish Date
2000
Start Page
38
End Page
44

Interchangeabelity of cytokine receptor signals during terminal myeloid differentiation: erythropoietin receptor (epor) signals support granulocytic differentiation and induction of myeloid gene expression

Hematopoietic cytokines and intracellular signals emanating from their cell surface receptors support the proliferation, viability and differentiation of bone marrow cells. The precise role of cytokine/cytokine receptor interactions in lineage-restricted hematopoietic differentiation is incompletely defined. To study lineage specificity of cytokine signal transduction in terminal hematopoietic differentiation, we examined EpoR function during granulocytic differentiation. A cell culture model for granulocyte-macrophage colony stimulating factor (GM-CSF)-mediated granulocytic differentiation was used to determine the ability of Epo to support terminal differentiation of committed myeloid cells, engineered to ectopically express the full-length EpoR by retrovirus-mediated gene transfer. The EpoR was introduced into a multipotential murine cell line EML, from which GM-CSF-responsive, promyelocytic EPRO cells were generated in vitro. Ectopic expression of EpoR in transduced EML cells and myeloid EPRO cells was confirmed by immunoprecipitation of EpoR and Western blotting. We investigated the function of ectopic EpoR expression in myeloid EPRO cells to determine whether Epo/EpoR interaction can mediate granulocytic differentiation and the induction of myeloid gene expression. In EPRO cells expressing EpoR, Epo supported morphologic differentiation into neutrophils in a manner similar to GM-CSF. These results indicate that Epo can deliver differentiative signals along a nonerythroid lineage, functionally replacing GM-CSF receptor signals that induce granulocytic differentiation in this system. Morphologic granulocytic differentiation in response to Epo was associated with induction of surface CDllb/CD18 (Mac-1) expression, a myeloid marker detected by flow cytometry. To determine whether EpoR signals can functionally mediate activation of myeloid gene expression in differentiating EPRO cells, we examined the ability of Epo to induce myeloid-specific gene expression. Northern analysis showed that Epo-induced granulocytic differentiation was associated with activation of expression of genes encoding neutrophil specific granule proteins lactoferrin and gelatinase as well as myeloid transcription factor C/EBP e. These findings provide evidence for interchangeability of cytokine receptor signals that mediate terminal differentiation of committed myeloid cells and myeloid gene expression.

Authors
Arcasoy, M; Maun, N; Ferez, L; Forget, B; Berliner, N
MLA Citation
Arcasoy, M, Maun, N, Ferez, L, Forget, B, and Berliner, N. "Interchangeabelity of cytokine receptor signals during terminal myeloid differentiation: erythropoietin receptor (epor) signals support granulocytic differentiation and induction of myeloid gene expression." Blood 96.11 PART II (2000): 137b-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
137b

Molecular diagnosis of hemoglobinopathies and other red blood cell disorders.

This article provides an overview of the techniques currently available for the molecular diagnosis of hemoglobinopathies and other inherited erythrocyte disorders. Advances in both clinical practice and molecular biology have permitted rapid genetic diagnosis of many of these disorders. In turn, rapid diagnosis has led to improvements in prenatal diagnosis and in early detection of at-risk individuals, permitting appropriate prenatal counseling to at-risk couples, allowing for appropriate patient education, and improving clinical outcome.

Authors
Arcasoy, MO; Gallagher, PG
MLA Citation
Arcasoy, MO, and Gallagher, PG. "Molecular diagnosis of hemoglobinopathies and other red blood cell disorders." Semin Hematol 36.4 (October 1999): 328-339. (Review)
PMID
10530715
Source
pubmed
Published In
Seminars in Hematology
Volume
36
Issue
4
Publish Date
1999
Start Page
328
End Page
339

A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation.

The erythropoietin receptor (EpoR) has been previously shown to contain a cytoplasmic C-terminal negative regulatory domain, experimental deletion or mutation of which leads to increased sensitivity of expressing cells to the effects erythropoietin (Epo). We have studied a naturally occurring C-terminal truncation mutant of the human EpoR by stably transfecting the growth factor-dependent hematopoietic tissue culture cell line 32D with expression plasmids containing either the wildtype or mutant human EpoR cDNA, thus rendering the cells dependent on Epo for viability and proliferation. In Epo dose-response assays, cells expressing the mutant EpoR displayed hyperresponsiveness to Epo compared with cells expressing comparable numbers of the wild-type EpoR cultured in the presence of fetal bovine serum. We investigated whether enhanced Epo sensitivity of cells expressing the truncated EpoR is associated with alteration in Epo receptor-mediated activation of Stat5, which could have a role in Epo-induced proliferation. Although maximal Stat5 activation in response to a given concentration of Epo was comparable in 32D cells expressing the wild-type or truncated EpoRs, the time course of Epo-induced Stat5 activation was very different. Gel-mobility shift studies revealed the presence of Stat5 DNA-binding activity in nuclear and cytoplasmic extracts of cells expressing the truncated EpoR for a significantly longer time than that observed in similar extracts of cells expressing the wild-type EpoR consistent with decreased rate of inactivation of Stat5 in cells expressing the mutant EpoR. Epo-dependent tyrosine phosphorylation of both Stat5 and Jak2 was also substantially prolonged in cells expressing the truncated EpoR. These results suggest a role for Stat5 in regulation of Epo-mediated cell growth and implicate altered kinetics of Epo-induced Jak2 and Stat5 activation in the pathogenesis of familial erythrocytosis associated with this naturally occurring EpoR gene mutation.

Authors
Arcasoy, MO; Harris, KW; Forget, BG
MLA Citation
Arcasoy, MO, Harris, KW, and Forget, BG. "A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation." Exp Hematol 27.1 (January 1999): 63-74.
PMID
9923445
Source
pubmed
Published In
Experimental Hematology
Volume
27
Issue
1
Publish Date
1999
Start Page
63
End Page
74

The distal cytoplasmic domain of the erythropoietin receptor induces granulocytic differentiation in 32D cells.

The role of hematopoietic growth factors in lineage commitment and differentiation is unclear. We present evidence that heterologous expression of an erythroid specific receptor allows granulocytic differentiation of a myeloid cell line. We have previously characterized a truncation mutant of the erythropoietin receptor (EpoR), which is associated with familial erythrocytosis (Blood 89:4628, 1997). This truncated EpoR lacks the distal 70 amino acids of the cytoplasmic domain. To study the functional role of this distal receptor domain, 32D cells, a murine interleukin-3 (IL-3)-dependent myeloid line, were transfected with the wild-type EpoR (32D/EpoR WT) or the truncated EpoR (32D/EpoR FE). 32D cells expressing either the full-length or truncated EpoR display equivalent proliferative rates in saturating concentrations of Epo. There is a dramatic difference in maturational phenotype between the two cell lines, however. The 32D/EpoR FE cells and mock transfected 32D cells have an immature, monoblastic morphology and do not express the primary granule protein myeloperoxidase. The 32D/EpoR WT cells, on the other hand, demonstrate granulocytic differentiation with profuse granulation, mature, clumped chromatin, and myeloperoxidase expression. There is no evidence of erythroid differentiation in 32D cells transfected with either the full-length or truncated EpoR. Treatment of the cells with the specific Jak2 inhibitor tyrphostin AG 490 inhibits myeloid differentiation driven by the distal EpoR. We conclude that: (1) the distal cytoplasmic domain of the EpoR is able to induce a specific myeloid differentiation signal distinct from mitogenic signaling, and (2) these data extend to myelopoiesis the growing body of evidence that the cellular milieu, not the specific cytokine receptor, determines the specificity of differentiation after cytokine receptor activation.

Authors
Harris, KW; Hu, XJ; Schultz, S; Arcasoy, MO; Forget, BG; Clare, N
MLA Citation
Harris, KW, Hu, XJ, Schultz, S, Arcasoy, MO, Forget, BG, and Clare, N. "The distal cytoplasmic domain of the erythropoietin receptor induces granulocytic differentiation in 32D cells." Blood 92.4 (August 15, 1998): 1219-1224.
PMID
9694710
Source
pubmed
Published In
Blood
Volume
92
Issue
4
Publish Date
1998
Start Page
1219
End Page
1224

Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene.

Familial erythrocytosis (familial polycythemia) inherited as an autosomal dominant trait has recently been reported to be associated with mutations in the gene encoding the erythropoietin receptor (EpoR) in a small number of families. We studied a new kindred with dominantly inherited familial erythrocytosis associated with heterozygosity for a deletion of seven nucleotides between positions 5985 and 5991 in exon 8 of the EpoR gene, resulting in an EpoR peptide that is truncated by 59 amino acids at its C-terminus. A 7-bp direct repeat is present in the normal EpoR gene at the site of this mutation, consistent with the slipped mispairing model for the generation of short deletions during DNA replication. Hypersensitivity to Epo of erythroid progenitors from an affected individual was observed in in vitro methylcellulose cultures, as indicated by more numerous and larger colonies compared with those of a control subject. To study mutant EpoR function, the cDNA encoding the mutant EpoR was synthesized by reverse transcription-polymerase chain reaction of peripheral blood RNA from the proband and stably tranfected into murine interleukin-3-dependent 32D cells. Epo dose-response assays showed that cells expressing the mutant EpoR displayed fivefold to 10-fold increased sensitivity to Epo compared with cells expressing similar numbers of the wild-type EpoR.

Authors
Arcasoy, MO; Degar, BA; Harris, KW; Forget, BG
MLA Citation
Arcasoy, MO, Degar, BA, Harris, KW, and Forget, BG. "Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene." Blood 89.12 (June 15, 1997): 4628-4635.
PMID
9192789
Source
pubmed
Published In
Blood
Volume
89
Issue
12
Publish Date
1997
Start Page
4628
End Page
4635

High levels of human gamma-globin gene expression in adult mice carrying a transgene of deletion-type hereditary persistence of fetal hemoglobin.

Persistent expression of the gamma-globin genes in adults with deletion types of hereditary persistence of fetal hemoglobin (HPFH) is thought to be mediated by enhancer-like effects of DNA sequences at the 3' breakpoints of the deletions. A transgenic mouse model of deletion-type HPFH was generated by using a DNA fragment containing both human gamma-globin genes and HPFH-2 breakpoint DNA sequences linked to the core sequences of the locus control region (LCR) of the human beta-globin gene cluster. Analysis of gamma-globin expression in six HPFH transgenic lines demonstrated persistence of gamma-globin mRNA and peptides in erythrocytes of adult HPFH transgenic mice. Analysis of the hemoglobin phenotype of adult HPFH transgenic animals by isoelectric focusing showed the presence of hybrid mouse alpha2-human gamma2 tetramers as well as human gamma4 homotetramers (hemoglobin Bart's). In contrast, correct developmental regulation of the gamma-globin genes with essentially absent gamma-globin gene expression in adult erythroid cells was observed in two control non-HPFH transgenic lines, consistent with autonomous silencing of normal human gamma-globin expression in adult transgenic mice. Interestingly, marked preferential overexpression of the LCR-distal (A)gamma-globin gene but not of the LCR-proximal (G)gamma-globin gene was observed at all developmental stages in erythroid cells of HPFH-2 transgenic mice. These findings were also associated with the formation of a DNase I-hypersensitive site in the HPFH-2 breakpoint DNA of transgenic murine erythroid cells, as occurs in normal human erythroid cells in vivo. These results indicate that breakpoint DNA sequences in deletion-type HPFH-2 can modify the developmentally regulated expression of the gamma-globin genes.

Authors
Arcasoy, MO; Romana, M; Fabry, ME; Skarpidi, E; Nagel, RL; Forget, BG
MLA Citation
Arcasoy, MO, Romana, M, Fabry, ME, Skarpidi, E, Nagel, RL, and Forget, BG. "High levels of human gamma-globin gene expression in adult mice carrying a transgene of deletion-type hereditary persistence of fetal hemoglobin." Mol Cell Biol 17.4 (April 1997): 2076-2089.
PMID
9121456
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
17
Issue
4
Publish Date
1997
Start Page
2076
End Page
2089

Hematologic disorders and nonimmune hydrops fetalis.

Hematologic disorders are implicated in approximately 10% to 27% of cases of nonimmune hydrops fetalis. In almost all of these disorders, anemia leading to heart failure, edema, ascites, and anasarca is the final common denominator. The etiology of the anemia in these cases can be conveniently divided into two categories: (1) excessive erythrocyte loss by hemolysis or hemorrhage, and (2) erythrocyte underproduction. The former include intrinsic erythrocyte abnormalities such as alpha-thalassemia and glucose-6-phosphate dehydrogenase deficiency, and conditions with excessive fetal blood loss such as fetomaternal hemorrhage and twin-twin transfusion. The latter include bone marrow replacement syndromes and conditions associated with failure of erythrocyte production. The presentation, diagnosis, and management of hematologic disorders associated with nonimmune hydrops fetalis are reviewed.

Authors
Arcasoy, MO; Gallagher, PG
MLA Citation
Arcasoy, MO, and Gallagher, PG. "Hematologic disorders and nonimmune hydrops fetalis." Semin Perinatol 19.6 (December 1995): 502-515. (Review)
PMID
8822334
Source
pubmed
Published In
Seminars in Perinatology
Volume
19
Issue
6
Publish Date
1995
Start Page
502
End Page
515

Spontaneous delta- to beta-globin switching in K562 human leukemia cells.

Previous analysis of the hemoglobin phenotype of the K562 human erythroleukemia cell line showed regulated expression of the epsilon-, zeta-, gamma-, alpha-, and delta-globin genes. Expression of the beta-globin genes has not been previously detected in this cell line. In this report, we describe the isolation of a variant of the K562 cell line that actively expresses beta-globin messenger RNA (mRNA) and polypeptide and shows greatly reduced expression of the delta-globin genes. This phenotype developed spontaneously in culture while two other K562 isolates grown under the same culture conditions have not undergone the same delta- to beta-globin switch. Analysis of this unique K562 variant shows that a construct containing a beta-globin promoter is quite active upon transient transfection into these cells. This finding suggests that the activation of the endogenous beta-globin genes results from changes in the trans-acting environment of these cells. The regulation of the beta-globin genes in this variant is characterized by a paradoxical decrease in the level of beta-globin mRNA after exposure to hemin. Other globin genes of this variant are appropriately regulated and show increased expression after hemin induction. Further study of this variant may shed light on mechanisms of gene regulation that are involved in hemoglobin switching.

Authors
Mookerjee, B; Arcasoy, MO; Atweh, GF
MLA Citation
Mookerjee, B, Arcasoy, MO, and Atweh, GF. "Spontaneous delta- to beta-globin switching in K562 human leukemia cells." Blood 79.3 (February 1, 1992): 820-825.
PMID
1732019
Source
pubmed
Published In
Blood
Volume
79
Issue
3
Publish Date
1992
Start Page
820
End Page
825

Nocturnal penile tumescence in cigarette smokers with erectile dysfunction.

We examined the relationship between cigarette smoking and erectile physiology in 314 men with erectile dysfunction. All of the men studied were currently cigarette smokers. Evaluations included interviews, physical examinations, and polysomnographic assessment of sleep-related erections. Penile rigidity during nocturnal erection inversely correlated with the number of cigarettes smoked per day. Smoking was also associated with indices of impairment on autonomic function tests and some measures of penile blood pressure. The group of men who smoked the most (more than 40 cigarettes per day) had the fewest minutes of nocturnal tumescence and detumesced fastest. These data are discussed with respect to the results of studies performed in dogs that demonstrated smoking-related reduction in arterial flow and venous restriction. Our findings suggest that smoking may further compromise penile physiology in men experiencing difficulty in maintaining erections long enough for satisfactory intercourse.

Authors
Hirshkowitz, M; Karacan, I; Howell, JW; Arcasoy, MO; Williams, RL
MLA Citation
Hirshkowitz, M, Karacan, I, Howell, JW, Arcasoy, MO, and Williams, RL. "Nocturnal penile tumescence in cigarette smokers with erectile dysfunction." Urology 39.2 (February 1992): 101-107.
PMID
1736499
Source
pubmed
Published In
Urology
Volume
39
Issue
2
Publish Date
1992
Start Page
101
End Page
107

Regulated expression of p18, a major phosphoprotein of leukemic cells.

p18 is a phosphoprotein that is present in great abundance in acute leukemia blasts and in less abundance in proliferating lymphocytes. This protein undergoes major changes in its state of phosphorylation upon induction of differentiation of leukemic cells in culture. The same protein appears to be involved in a variety of other cellular processes that include regulation of hormone secretion, T cell activation, muscle differentiation, and brain development. In this report, we describe our studies of the regulation of expression of this gene in leukemic cells. We show that the expression of this gene is markedly reduced upon induction of differentiation of a variety of leukemic cells in culture. We use a cDNA clone that we constructed earlier which encodes this protein as a probe to isolate the human chromosomal p18 gene. We characterize the 5' end of this gene in detail and identify its promoter element. We also identify a regulatory element in the first intervening sequence (IVS-1) of this gene which loses its DNase I hypersensitivity upon induction of differentiation of leukemic cells in culture. Our DNase I footprinting experiments demonstrate nuclear protein binding to multiple sequence motifs within its promoter element and its IVS-1 regulatory element. Functional studies using a transient expression system show that deletion of these sequence motifs has profound effects on the expression of this gene. These studies begin to shed some light on the mechanism of regulation of a gene that may be involved in control of cell growth and differentiation and in a variety of other vital cellular processes.

Authors
Luo, XN; Arcasoy, MO; Brickner, HE; Mistry, S; Schechter, AD; Atweh, GF
MLA Citation
Luo, XN, Arcasoy, MO, Brickner, HE, Mistry, S, Schechter, AD, and Atweh, GF. "Regulated expression of p18, a major phosphoprotein of leukemic cells." J Biol Chem 266.31 (November 5, 1991): 21004-21010.
PMID
1939149
Source
pubmed
Published In
The Journal of biological chemistry
Volume
266
Issue
31
Publish Date
1991
Start Page
21004
End Page
21010

Prevalence of sleep apnea in men with erectile dysfunction.

Sleep studies were performed on 1,025 patients complaining of erectile dysfunction. In addition to standard measures of sleep stage and nocturnal penile tumescence, respiratory activity was evaluated. The number of episodes of sleep apnea per hour (Apnea Index--AI) was calculated for each patient. The overall prevalence of sleep apnea activity in this sample was: 43.8 percent with AI greater than or equal to 5; 27.9 percent with AI greater than or equal to 10; and 19.6 percent with AI greater than or equal to 15. These results confirm that sleep apnea activity is common in men with erectile dysfunction. This high prevalence also indicates that further study is needed to elucidate pathophysiology of erectile failure in men with sleep apnea.

Authors
Hirshkowitz, M; Karacan, I; Arcasoy, MO; Acik, G; Narter, EM; Williams, RL
MLA Citation
Hirshkowitz, M, Karacan, I, Arcasoy, MO, Acik, G, Narter, EM, and Williams, RL. "Prevalence of sleep apnea in men with erectile dysfunction." Urology 36.3 (September 1990): 232-234.
PMID
2392814
Source
pubmed
Published In
Urology
Volume
36
Issue
3
Publish Date
1990
Start Page
232
End Page
234

The prevalence of periodic limb movements during sleep in men with erectile dysfunction.

Authors
Hirshkowitz, M; Karacan, I; Arcasoy, MO; Acik, G; Williams, RL
MLA Citation
Hirshkowitz, M, Karacan, I, Arcasoy, MO, Acik, G, and Williams, RL. "The prevalence of periodic limb movements during sleep in men with erectile dysfunction." Biol Psychiatry 26.5 (September 1989): 541-544.
PMID
2790095
Source
pubmed
Published In
Biological Psychiatry
Volume
26
Issue
5
Publish Date
1989
Start Page
541
End Page
544
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